Nivolumab plus Cabozantinib in Metastatic Renal Cell Carcinoma: Real-World Evidence from the International ARON-1 Study

Maria T Bourlon^1,2Luca Galli³Enrique Grande⁴Se Hoon Park⁵Bohuslav Melichar⁶Timothy J Schieber⁷Maria José Juan-Fita⁸YÜKSEL ÜRÜN⁹Javier Molina-Cerrillo¹⁰Teresa Alonso-Gordoa¹⁰Ugo De Giorgi¹¹Jakub Kucharz¹²Esther Pérez Calabuig¹³Vincenza Conteduca¹⁴Tarek Taha^15,16Pasquale Rescigno¹⁷Hussam Abu-Sini¹⁸Gian Paolo Spinelli¹⁹Ray Manneh²⁰Alessia Salfi²¹Dipen Bhuva²²Paola Valdez-Sandoval¹Sofia Mendez-Bribiesca¹Ondrej Fiala^22,23Sebastiano Buti^24,25Fernando Sabino Marques Monteiro^26,27Aristotle Bamias²⁸Marwan Ghosn²⁹Francesco Massari^30,31Jawaher Ansari³²Matteo Santoni^33*

• ¹Department of Hemato-Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
• ²Universidad Panamericana, Escuela de Medicina, Mexico City, Mexico
• ³Oncology Unit 2, University Hospital Pisa, Pisa, Italy
• ⁴Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain
• ⁵Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
• ⁶Department of Oncology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Olomouc, Czechia
• ⁷Division of Medical Oncology, Department of Internal Medicina, Kansas Cancer Center, Westwood, United States
• ⁸Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain
• ⁹Department of Medical Oncology, Ankara University Faculty of Medicine, Ankara, Türkiye
• ¹⁰Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Madrid, Spain
• ¹¹Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
• ¹²Department of Uro-Oncology, Maria Sklodowska-Curie National Research Institute of Oncology Warsaw, Warsaw, Poland
• ¹³Medical Oncology Department, CHU Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain
• ¹⁴Unit of Medical Oncology and Biomolecular Therapy and C.R.E.A.T.E - Center for Research and Innovation Medicine, Department. of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy
• ¹⁵Institute of Cancer Research (ICR), London, England, United Kingdom
• ¹⁶Royal Marsden NHS Foundation Trust, London, Westminster, United Kingdom
• ¹⁷Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom
• ¹⁸Oncology Institute, Rambam Healthcare campus, Haifa, Israel
• ¹⁹UOC Oncologia Territoriale Ausl Latina, Aprilia, Italy
• ²⁰Clinical Oncology, Sociedad de Oncología y Hematología del Cesar, Valledupar, Colombia
• ²¹Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
• ²²Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czechia
• ²³Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Plzen, Plzen Region, Czechia
• ²⁴Medical Oncology Unit, University Hospital of Parma, Parma, Emilia-Romagna, Italy
• ²⁵Department of Medicine and Surgery, University of Parma, Parma, Emilia-Romagna, Italy
• ²⁶Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Rio Grande do Sul, Brazil
• ²⁷Oncology and Hematology Department, Hospital Sírio Libanês, Brasília, Brazil
• ²⁸2nd Propaedeutic Department of Internal Medicine, ATTIKON University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
• ²⁹Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon
• ³⁰Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ³¹Department of Medical and Surgical Sciences, University of Bologna, Bologna, Emilia-Romagna, Italy
• ³²Medical Oncology, Tawam Hospital, Al Ain, United Arab Emirates
• ³³Medical Oncology Unit, Macerata Hospital, Macerata, Italy

Introduction: Four approved immune-based combinations for untreated metastatic renal carcinoma have demonstrated survival benefits. The ARON-1 study (NCT05287464) analyzed real-world data of patients with metastatic renal cell carcinoma receiving first-line immuno-oncology combinations. This sub-analysis is focused on the nivolumab plus cabozantinib effectiveness. Methods: We conducted a retrospective study across 52 centers in 17 countries, including patients with metastatic renal carcinoma treated with first-line nivolumab plus cabozantinib, regardless of histologic characteristics, performance status, or risk by IMDC prognostic model. Patients with incomplete medical data were excluded. The primary objective of this sub-analysis of the ARON-1 study was to evaluate the real-world effectiveness and safety. Results: A total of 333 patients were treated with nivolumab plus cabozantinib, clinical characteristics included ECOG performance status ≥2 20%, non-clear cell histology 16%, sarcomatoid de-differentiation 12%, and poor-risk by IMDC 28%. At a median follow-up of 15.9 months (95%CI 11.2-44.0), the median overall survival was not reached (40.0-NR), the probability of survival at 2 years was 75%, while median progression free survival was 33.7 months (95%CI 21.1-38.9). In the entire cohort, an objective response was observed in 58%, with 6% complete responses, and a median duration of response of 38.9 months (95%CI 33.7-NR). At multivariate analysis, adverse prognostic factors for overall survival included ECOG performance status ≥2, sarcomatoid de-differentiation, brain and bone metastases, and poor IMDC group. In the safety analysis, the incidence of grade 3 or higher toxicity was 37%, with hypertension and hand-foot syndrome being the most frequent adverse events. Conclusion: The findings in the present real-world study reaffirm the clinical benefits and safety of the nivolumab plus cabozantinib combination across all subgroups, including populations that are generally excluded from clinical trials for whom data is often missing. Poor performance status, sarcomatoid de-differentiation, bone or central nervous system metastases and IMDC poor risk group were confirmed as negative prognostic factors.